Biology subjects

Shan, K. Z.

Publications and source records attributed to Shan, K. Z..

5 recordsLinked to original sources

bioRxiv2026

Cannabidiol Inhibits PIEZO Channels to Mitigate Red Blood Disorders

Hyperactivity of the mechanosensitive ion channel PIEZO1 promotes pathologic Ca{superscript 2} overload in red blood cells (RBCs), driving dehydration, TMEM16F-dependent phosphatidylserine (PS) exposure, microparticle shedding, and increased thrombotic and vaso-occlusive risks in hereditary xerocytosis (HX) and sickle cell disease (SCD). However, clinically deployable PIEZO inhibitors to treat these blood disorders are lacking. Here we report that cannabidiol (CBD), a non-psychoactive cannabinoid commonly used in SCD patients for pain management, inhibits PIEZO1 activity and restores aberrant mechanotransduction in HX and SCD RBCs. Micromolar concentrations of CBD blocks PIEZO1 currents and suppresses PIEZO1-mediate Ca{superscript 2} entry. In HX and SCD RBCs, CBD attenuates PIEZO1-TMEM16F coupling, thereby reducing PS exposure, microparticle release, thrombin generation, RBC-endothelium adhesion, and sickling. Beyond RBCs, CBD also blocks PIEZO2 currents and PIEZO2-dependent mechanical sensation in mice, suggesting broader effects of CBD-mediated PIEZO inhibition on nociceptive functions. Together, our findings identify CBD as a potent PIEZO inhibitor that restores calcium and membrane homeostasis, supporting the repurposing of CBD or the development of CBD-derived, PIEZO-selective analogs as a promising disease-modifying strategy for SCD, HX, and other PIEZO-mediated mechanosensing disorders. HighlightsO_LICBD inhibits PIEZO channels and disrupts the PIEZO1-TMEM16F axis in diseased RBCs C_LIO_LICBD shows a therapeutic window to prevent PS exposure and translational promise for HX and SCD C_LI

pharmacology and toxicology↗

bioRxiv2025

Targeting PIEZO1-TMEM16F Coupling to Mitigate Sickle Cell Disease Complications

A deeper understanding of sickle cell disease (SCD) pathophysiology is critical for identifying novel therapeutic targets. A hallmark of SCD is abnormal phosphatidylserine (PS) exposure on sickle red blood cells (RBCs), which contributes to anemia, thrombosis, and vaso-occlusive crises (VOC). However, the mechanisms underlying this excessive PS exposure remain unclear. Here, we identify TMEM16F, a Ca2+-activated lipid scramblase, as a key mediator of PS exposure downstream of Ca2+ influx through the mechanosensitive channel PIEZO1 in sickle RBCs. Electrophysiology, imaging and flow cytometry reveal that deoxygenation-induced sickling promotes PIEZO1 activation, triggering Ca2+ entry, TMEM16F activation, and PS exposure. This cascade enhances PS+ microparticle release, thrombin generation, and RBC adhesion to endothelial cells. Notably, partial PIEZO1 inhibition with benzbromarone, an anti-gout drug, suppresses these changes. Our findings thus define a previously unrecognized mechanotransduction pathway in sickle RBCs and propose a unique therapeutic strategy to mitigate hypercoagulability and vaso-occlusion associated with SCD. Brief SummaryEnhanced PIEZO1 activation in sickle red blood cells promotes TMEM16F scramblase-mediated phosphatidylserine exposure and subsequent sickle cell disease complications. Disrupting this coupling presents a potential therapeutic strategy.

physiology↗

bioRxiv2025

PIEZO1 Drives Trophoblast Fusion and Placental Development

PIEZO1, a mechanosensor1,2 in endothelial cells, plays a critical role in fetal vascular development during embryogenesis3,4. However, its expression and function in placental trophoblasts remain unexplored. Here, we demonstrate that PIEZO1 is expressed in placental villus trophoblasts, where it is essential for trophoblast fusion and placental development. Mice with trophoblast-specific PIEZO1 knockout exhibit embryonic lethality without obvious vascular defects. Instead, PIEZO1 deficiency disrupts the formation of the syncytiotrophoblast layer in the placenta. Mechanistically, PIEZO1-mediated calcium influx activates TMEM16F lipid scramblase, facilitating the externalization of phosphatidylserine, a key "fuse-me" signal for trophoblast fusion5,6. These findings reveal PIEZO1 as a crucial mechanosensor in trophoblasts and highlight its indispensable role in trophoblast fusion and placental development, expanding our understanding of PIEZO1s functions beyond endothelial cells during pregnancy.

cell biology↗

bioRxiv2023

Endothelial TMEM16F lipid scramblase regulates angiogenesis

Dynamic loss of lipid asymmetry through the activation of TMEM16 Ca2+-activated lipid scramblases (CaPLSases) has been increasingly recognized as an essential membrane event in a wide range of physiological and pathological processes, including blood coagulation, microparticle release, bone development, pain sensation, cell-cell fusion, and viral infection. Despite the recent implications of TMEM16F CaPLSase in vascular development and endothelial cell-mediated coagulation, its signaling role in endothelial biology remains to be established. Here, we show that endothelial TMEM16F regulates in vitro and in vivo angiogenesis through intracellular signaling. Developmental retinal angiogenesis is significantly impaired in TMEM16F deficient mice, as evidenced by fewer vascular loops and larger loop areas. Consistent with our in vivo observation, TMEM16F siRNA knockdown in human umbilical vein endothelial cells compromises angiogenesis in vitro. We further discovered that TMEM16F knockdown enhances VE-cadherin phosphorylation and reduces its expression. Moreover, TMEM16F knockdown also promotes Src kinase phosphorylation at tyrosine 416, which may be responsible for downregulating VE-cadherin expression. Our study thus uncovers a new biological function of TMEM16F in angiogenesis and provides a potential mechanism for how the CaPLSase regulates angiogenesis through intracellular signaling.

physiology↗

bioRxiv2021

Functional coupling between TRPV4 channel and TMEM16F modulates human trophoblast fusion

TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase), is critical for placental trophoblast syncytialization, HIV infection, and SARS-CoV2-mediated syncytialization. How TMEM16F is activated during cell fusion is unclear. Here, we used trophoblasts as a model for cell fusion and demonstrated that Ca2+ influx through Ca2+ permeable transient receptor potential vanilloid channel TRPV4 is critical for TMEM16F activation and subsequent human trophoblast fusion. GSK1016790A, a TRPV4 specific agonist, robustly activates TMEM16F in trophoblasts. Patch-clamp electrophysiology demonstrated that TRPV4 and TMEM16F are functionally coupled within Ca2+ microdomains in human trophoblasts. Pharmacological inhibition or gene silencing of TRPV4 hindered TMEM16F activation and subsequent trophoblast syncytialization. Our study uncovers the functional expression of TRPV4 and a physiological activation mechanism of TMEM16F in human trophoblasts, thus providing us with novel strategies to regulate CaPLSase activity as a critical checkpoint of physiologically- and disease-relevant cell fusion events.

physiology↗